The many faces of CD8+ T cells in atherosclerosis

Duijn, Janine van; Kuiper, Johan; Slütter, Bram

doi:10.1097/mol.0000000000000541

Cited by 38 publications

(27 citation statements)

References 56 publications

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“…Some studies show no effect or a protective effect of CD8 T cells in atherosclerosis, whereas others report a proatherogenic effect [513]. A neutral or protective action is supported by unaltered atherosclerosis in ApoE −/− mice lacking antigen peptide transporter 1-(TAP1)-dependent MHC-I antigen presentation, despite the low number of CD8 + T cells in these animals [514].…”

Section: Adaptive Immunitymentioning

confidence: 99%

Immunobiology of Atherosclerosis: A Complex Net of Interactions

Herrero‐Fernández

Gómez-Bris

Somovilla-Crespo

et al. 2019

IJMS

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Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis. Int. J. Mol. Sci. 2019, 20, 5293 2 of 48 cytotoxic T lymphocytes at the interface between innate and adaptive immunity. Abundant evidence indicates that innate and adaptive immunity both play important roles in the onset and progression of atherosclerosis [1][2][3]. For example, Csf1 −/− mice, which lack macrophage colony stimulating factor (M-CSF, also known as CSF1) are less prone to developing atherosclerosis [4]. Moreover, mice lacking B and T cells (Rag1 −/− or Rag2 −/− mice lacking recombination-activating genes 1 or 2 or mice carrying the severe combined immunodeficiency (SCID) mutation) are resistant to atherosclerosis in the presence of mild hypercholesterolemia [5][6][7][8][9][10]. Int. J. Mol. Sci. 2019, 20, 5293 2 of 46 cells are cytotoxic T lymphocytes at the interface between innate and adaptive immunity. Abundant evidence indicates that innate and adaptive immunity both play important roles in the onset and progression of atherosclerosis [1][2][3]. For example, Csf1 −/− mice, which lack macrophage colony stimulating factor (M-CSF, also known as CSF1) are less prone to developing atherosclerosis [4]. Moreover, mice lacking B and T cells (Rag1 −/− or Rag2 −/− mice lacking recombination-activating genes 1 or 2 or mice carrying the severe combined immunodeficiency (SCID) mutation) are resistant to atherosclerosis in the presence of mild hypercholesterolemia [5-10]. Atherosclerosis's PathophysiologyAtherosclerosis is a chronic inflammatory disease of large and medium-sized arteries [20], characterized by endothelial dysfunction and the accumulation of low-density lipoproteins (LDL), immune cells, and necrotic debris in the subendothelial space, resulting in the formation of an atherosclerotic plaque [21][22][23][24]. LDL deposition is more likely in regions with turbulent flow and low shear stress [25] sensed by the vascular endothelium [26]. Turbulent flow modulates endothelial transcrip...

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Section: Adaptive Immunitymentioning

confidence: 99%

Immunobiology of Atherosclerosis: A Complex Net of Interactions

Herrero‐Fernández

Gómez-Bris

Somovilla-Crespo

et al. 2019

IJMS

View full text Add to dashboard Cite

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“…CD8 cytotoxic T cells are present in human atherosclerotic lesions, as proven decades ago (123), and their number is linked with atherosclerosis pathophysiology (124). In the plaque, CD8 T cells exacerbate inflammation, and exert cytotoxic activity toward lesion-stabilizing cells, such as smooth muscle cells and ECs, driving the atherosclerosis progression and plaque instability (125). By contrast, it must be noted that CD8 T-cell subsets with immunomodulatory capacity which limit atherosclerosis are also present in the plaque (125).…”

Section: Functional Phenotypes Of T-cells Determine Atherosclerosis Pmentioning

confidence: 99%

Notch Signaling Regulates Immune Responses in Atherosclerosis

et al. 2019

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Atherosclerosis is a chronic autoimmune inflammatory disease that can cause coronary artery disease, stroke, peripheral artery disease, depending on which arteries are affected. At the beginning of atherosclerosis plasma lipoproteins accumulate in the sub-endothelial space. In response, monocytes migrate from the circulation through the endothelium into the intima where they differentiate into macrophages. These early events trigger a complex immune response that eventually involves many cellular subtypes of both innate and adaptive immunity. The Notch signaling pathway is an evolutionary conserved cell signaling system that mediates cell-to-cell communication. Recent studies have revealed that Notch modulate atherosclerosis by controlling macrophages polarization into M1 or M2 subtypes. Furthermore, it is known that Notch signaling controls differentiation and activity of T-helper and cytotoxic T-cells in inflammatory diseases. In this review, we will discuss the role of Notch in modulating immunity in the context of atherosclerosis and whether targeting Notch may represent a therapeutic strategy.

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“…Cytotoxic CD8 + T cells exert their inflammatory function by secreting cytokines, by performing cell-lysis via perforin, or granzyme-B and by inducing cell-death of their target cells through Fas-FasL interactions (7). CD8 + T cells might diminish the development of atherosclerotic lesions in early stages of the disease by killing macrophages and other antigen-presenting cells but they actually might promote lesion development by secreting pro-inflammatory cytokines (8). Thus, the contribution of CD8 + T cells to atherosclerosis seems context-dependent and remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Defective Autophagy in T Cells Impairs the Development of Diet-Induced Hepatic Steatosis and Atherosclerosis

et al. 2018

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Macroautophagy (or autophagy) is a conserved cellular process in which cytoplasmic cargo is targeted for lysosomal degradation. Autophagy is crucial for the functional integrity of different subsets of T cells in various developmental stages. Since atherosclerosis is an inflammatory disease of the vessel wall which is partly characterized by T cell mediated autoimmunity, we investigated how advanced atherosclerotic lesions develop in mice with T cells that lack autophagy-related protein 7 (Atg7), a protein required for functional autophagy. Mice with a T cell-specific knock-out of Atg7 (Lck-Cre Atg7f/f) had a diminished naïve CD4+ and CD8+ T cell compartment in the spleen and mediastinal lymph node as compared to littermate controls (Atg7f/f). Lck-Cre Atg7f/f and Atg7f/f mice were injected intravenously with rAAV2/8-D377Y-mPCSK9 and fed a Western-type diet to induce atherosclerosis. While Lck-Cre Atg7f/f mice had equal serum Proprotein Convertase Subtilisin/Kexin type 9 levels as compared to Atg7f/f mice, serum cholesterol levels were significantly diminished in Lck-Cre Atg7f/f mice. Histological analysis of the liver revealed less steatosis, and liver gene expression profiling showed decreased expression of genes associated with hepatic steatosis in Lck-Cre Atg7f/f mice as compared to Atg7f/f mice. The level of hepatic CD4+ and CD8+ T cells was greatly diminished but both CD4+ and CD8+ T cells showed a relative increase in their IFNγ and IL-17 production upon Atg7 deficiency. Atg7 deficiency furthermore reduced the hepatic NKT cell population which was decreased to < 0.1% of the lymphocyte population. Interestingly, T cell-specific knock-out of Atg7 decreased the mean atherosclerotic lesion size in the tri-valve area by over 50%. Taken together, T cell-specific deficiency of Atg7 resulted in a decrease in hepatic steatosis and limited inflammatory potency in the (naïve) T cell compartment in peripheral lymphoid tissues, which was associated with a strong reduction in experimental atherosclerosis.

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The many faces of CD8+ T cells in atherosclerosis

Abstract: Here we review the different roles of CD8 T cells in atherosclerosis and discuss possible treatment strategies targeting these cells to reduce atherosclerotic lesion burden.

Cited by 38 publications

References 56 publications

Immunobiology of Atherosclerosis: A Complex Net of Interactions

Immunobiology of Atherosclerosis: A Complex Net of Interactions

Notch Signaling Regulates Immune Responses in Atherosclerosis

Defective Autophagy in T Cells Impairs the Development of Diet-Induced Hepatic Steatosis and Atherosclerosis

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